Method of preparing steroids



United States Patent Ofi ice 3,366,653 Patented Jan. 30, 1968 ABSTRACTOF THE DISCLOSURE 1,2,8-methylene-l7u-hydroxyprogesterone and its 170:-acetate, having strongly estrogenic properties, are prepared from thecorresponding 1,2fi-methylene-5a-pregnanes by dehydrogenation withselenium dioxide, or 2,3- dichloro-5,=6-dicyanobenzoquinone, orchloranil.

This invention relates to a method of preparing derivatives of1,2;3-methylene-l7u-hydroxyprogesterone which will hereinafter beabbreviated as X:X and shown as wherein R is hydrogen or the acylradical of a carboxylic acid, R is hydrogen or methyl, R is hydrogen,zxor ii-methyl, or at or fl-fiuorine. All acyl radicals usual in steroidchemistry are suitable sources of acyl radicals R Preferred acylradicals contain one to eleven carbon atoms, as in acetic, propionic,capronic, enanthic, undecanoic acid and the like. These acyl radicalsalso may be substituted in the usual manner. Suitable substituted acylradicals of carboxylic acids having 1 to 11 C atoms are those ofphenylacetic acid, cyclopentylpropionic acid, the halo-acetic acids,aminoacetic acid, oxypropionic acid, etc.

The novel derivatives of X:X are characterized by superior gestationproducing effect when applied subcutaneously or orally.

The strong gestagenic effect of the novel derivatives of X:X is shown inthe following Table 1 with reference to X:X acetate (I) as compared tothe knOWn gestagenic agents IIIV. The gestagenic effect of the severalcompounds was determined in infantile female rabbits by the usualClauberg test.

TABLE 1 (II) l7a-hydroXyprogesterone-acetate 1.0 (III) 60: methyl 17ahydroxyprogesteroneacetate 0.1

(IV) 19-nor-l7a-hydroxyprogesterone-acetate 0.1

(V) l7zx-ethinyl-l9-nor-testerone 0.13

(VI) 6 chloro-6-dehydro-l7a-hydroxyprogesterone-acetate 0.03

The new derivatives of X:X are compounded with additives, carriers, andthe like as is conventional in pharmaceutical practice to facilitatetheir therapeutic application. Tablets, sugar coated pills, capsules,pills, sus pensions, and solutions of the active agents of the inventionmay be prepared by well-known methods.

The new derivatives of X:X of the formula wherein R R R are thesubstituents referred to above and may be prepared from1,2,8-methylene-steroids of the formula by methods known per se.Selenium dioxide, 2,3-dichloro- 5,6-dicyanobenzoquinone or chloranil arepreferred dehydrogenating agents. If there is a free l7a-hydroxyl groupin the starting material the corresponding ester may be formed with thedesired acid or with a reactive derivative, namely, acyl chlorides andother halides, anhydrides, esters to obtain an acyl radical at RConversely, an acyloxy radical initially present in position 17 may beremoved by saponification in a conventional manner. All the acidscommonly employed in steroid chemistry for esterifying steroid alcoholsmay be employed for esterification, and esters of all these acids may besaponified.

The compounds of Set-series and of the SB-series which are usefulstarting materials for synthesizing the compounds of the invention maybe produced from known compounds by known methods which are representedby the following formulas:

Example 1 One gram 1,2,8 methyIene-Sa-pregnane-I7a-ol-3,20-dione acetatewas dissolved in 20 ml. absolute benzene, and l g. 2,3 dichloro5,6-dicyanobenzoquinone was added. The mixture was refluxed. After 12hours, additional 0.5 g. 2,3-dichloro-5,6-dicyanobenzoquinone wereadded, and two further additions of 0.5 g. and 1.0 grams respectivelywere made at intervals of 12 hours. The reaction product was taken up inbenzene. Insoluble material was removed by filtration and washed withbenzene. The organic phase was washed successively with aqueous sodiumcarbonate solution, Water, and sodium chloride solution, and was thendried. It was evaporated in a vacuum to about 100 ml., andchromatographed on 100 g. silica gel. The adsorbed material was elutedwith a solution of ethyl acetate in methylene chloride, and 550 mg.crude 1, 2B- methylene-l7a-acetoxyprogesterone was recovered. Afterrecrystallization from diiosopropyl ether, there were ob tained 310 mg.of a pure product of melting point 19l.5- 192 C. E =12,600.

Example 2 When one gram 1,2/3-methyIene-Saregnane-17tx-ol-3, ZO-dionewas reacted in a manner analogous to the procedure of Example 1, therewere obtained 350 mg. 1,2,B- methylene 17ot-hydroxyprogesterone. M.P.190.5191.5 C. E =11,400.

While a preferred method of producing a compound X:X and derivativesthereof have been described and illustrated it is to be noted thatmodifications thereof may be made without departing from the scope andspirit of the invention as herein claimed.

We claim:

1. A method of preparing derivatives of X:X having the formula wherein Ris a member of the group consisting of hydrogen and the acyl radical ofa carboxylic acid; R is a member of the group consisting of hydrogen andmethyl; R is a member of the group consisting of hydrogen, 0:- fluorine,Si-fluorine, a-methyl, and ,B-methyl, which comprises dehydrogenating acompound of the formula t C O --o R1 R2 CH2 I O: i

References Cited UNITED STATES PATENTS 3,127,396 3/1964 Weichert et al.260-2395 ELBERT L. ROBERTS, Primary Examiner.

